Skin melanocytes and other pigment-producing cells accomplish their main physiological task of melanin biosynthesis inside highly specialized compartments known as melanosomes. Melanosomes belong to a group of functionally specialized, cell-type-specific organelles that are derived from the endosomal-lysosomal system and known as lysosome-related organelles (LROs). Defective melanosome biogenesis underlies several forms of oculocutaneous albinism, with its typical manifestations in skin (reduced tanning ability, increased risk of developing skin cancer) and eyes (reduced visual acuity, nystagmus), often as part of syndromes - such as Hermansky-Pudlak syndrome (HPS) - that also include clinical manifestations caused by defective biogenesis of other LROs. The short-term goal of this project is to understand the functional specialization of selected components of the molecular machinery for protein trafficking in the endosomal-lysosomal system of most cell types, such that these components can also mediate the biogenesis of cell-type-specific LROs such as melanosomes. For example, genetic defects in some of the genes encoding ubiquitously expressed subunits of Adaptor Protein (AP)-3 and Biogenesis of Lysosome-related Organelles Complex (BLOC)-1 cause various forms of HPS. In the first Specific Aim, we will characterize some poorly understood molecular determinants for AP-3 and BLOC-1 function in melanosome biogenesis. In the second Specific Aim, we will characterize novel components of this molecular machinery. In the third Specific Aim, we will attempt to define the existence of novel LROs in other cell types.